........................................................... and Clinical Characteristics Introduction...........................................................................................................................................................................15 Conclusion .....................................................................................16 References ........................................................................5 Molecular Features ........................................7 Potential Molecular Targets .................................................................................................................................................................................................................................................................................................13 Prognostic Factors ...........6 Defining Triple-Negative Breast Cancer ...................................................8 Identifying Patients ......................3 Risk Factors ...........13 Recurrence Patterns ........6 Basal-like Breast Cancer ................................................9 Clinical and Biologic Characteristics .......3 Race and Ethnicity .............................................................................................................2 Age..............1 Epidemiology and Risk Factors....................................................................15 Clinical Management ...17 ......3 Heredity ........................................................Triple-Negative Breast Cancer: Understanding the Molecular......................................15 Current Clinical Practices .....6 Breast Cancer Phenotypes................................................................ Biologic..........................................11 Recurrence.....................4 Influencing Risk .......................................................................................................


Biologic. more than 2.1 In 2010.5 million women are living with a history of breast cancer. invasive breast cancer was classified based on histology.3-5 Until recently. an estimated 207.Triple-Negative Breast Cancer Understanding the Molecular.1. In addition to the options of surgery and radiotherapy for appropriate candidates. and prognoses. and Clinical Characteristics In the United States. and the expression of estrogen receptor (ER) and progesterone receptor (PR) status. distinct subtypes within this highly heterogeneous disease exhibit diverse natural histories. for which patients typically receive ER-targeted therapy with or without chemotherapy Introduction 1 .3 More recently. emphasizing the magnitude of this public health concern. responses to therapy. the expression of HER2 (also known as Erb-B2 or ERBB2) has been added to the routine pathological evaluation of breast cancer. clinical decisions for patients with breast cancer are now based on 3 broad characteristic subgroups: I Hormone receptor-positive tumors. and an estimated 39.2 Although great progress has been made in recent years and the overall 5-year survival of breast cancer is 89%.1. grade.840 will die of their disease.090 women in the United States will be diagnosed with invasive breast cancer.

Generalized receptor expression in breast tumors. -10% characteristics of triple-negative HER2+ HER2breast cancer. 75%-80% I I Epidemiology and Risk Factors Figure 1. the basal-like breast cancers. The clinical need for optimal therapy for patients with triple-negative breast cancer drives a growing investigational interest. These differences are underscored in women with triple-negative 2 . PR. HER2-). biologic. and HER2 30. prognosis phenotype.14-16 Specifically. status.4. of breast tumors are characterized as tripleless progress has been made in treating the worst negative (ER-. Biologic. PR-.7 Today. PR+ improve outcomes for patients. PR+.11-13 Approximately 10% to 15% of all breast cancers are triple-negative for the hormonal and HER2 receptors.15 This monograph will review % of Breast Cancer Cases the current knowledge of the HER2+ ER2+ molecular. which translates into almost which most often have a negative ER. and clinical ER+. Research is 7%-10% 10%-15% ongoing in this field. PR-. due to the lack of an established therapeutic target6. genome-wide microarray analysis allows a further refined classification of breast cancers into 5 Between 10% and 15% main molecular groups (see page 6).8-13 Triple-negative breast cancer is highly aggressive and has a poor prognosis. for which patients are eligible to receive a HER2-targeted therapy Both ER. which translates into almost 30.6 Between 10% and 15% of breast tumors are characterized as triple-negative (ER-.8.Triple-Negative Breast Cancer Understanding the Molecular.000 cases annually. HER2-).8. triplenegative breast cancer exhibits an earlier pattern of metastases and worse overall and disease-free survival than other breast cancer subtypes. PR-.000 cases annually (Figure 1). and Clinical Characteristics HER2-positive tumors. Unfortunately. and it is hoped that the expanded understanding of the basic science and clinical characteristics of triple-negative breast cancer will lead to strategies that will ER+.and PR-negative and HER2-negative tumors (known as triple-negative breast cancer) for which the only available systemic treatment is chemotherapy.18 Breast cancer is a highly heterogeneous disease that varies in incidence and mortality across demographic groups. 7%-10% ER-.9.

8. In addition. Risk Factors In addition to demographic features.358 California women diagnosed with breast cancer between 1999 and 2003 found that the median age at diagnosis for those with triple-negative tumors was 54 years of age.10. has poorly differentiated histology.8 Race and Ethnicity When considering all breast cancer subtypes.8 Even when potential socio-cultural factors are excluded.53 times more likely to in younger women than other types of breast cancer. in some studies.8. and a high mitotic index.breast cancer.1 African American women also have a higher mortality from triple-negative breast cancer than others. One large analysis of 92. African American ethnicity is a significant independent predictor of reduced breast cancer survival.8 The California breast cancer occurs Cancer Registry study also found that women younger significantly more often than 40 years of age were 1.21. breast cancer is more common in white women than other racial and ethnic groups in this country. Hispanic women have been found to have a higher incidence of triple-negative breast cancer than white women.22 The factors associated with reproduction include: early onset of menarche. Of the women with triple-negative disease. several population-based studies have reported that African American women have a higher mortality. young age at first-term pregnancy.10.10.17. Common characteristics reported among large cohorts of triple-negative breast cancer patients include younger age and lower socioeconomic status.19 Despite the lower incidence of breast cancer in general in African American women. However. various reproductive and anthropometric characteristics increase the risk of triple-negative breast cancer.18 Age Several large analyses have found that triple-negative breast cancer occurs significantly more often in younger women than other types of breast cancer. which was the median age at diagnosis for those patients found that triple-negative with other subtypes of breast cancer.8.18. be diagnosed with triple-negative disease than women between the ages of 60 and 69 years. triple-negative breast cancer also presents in appreciable numbers of younger white women. triple-negative breast cancer is often diagnosed at a more advanced stage. as well as older African American women. supporting a rationale for genetic or biologic factors impacting this population. as do Hispanic women. Several large analyses have 63% were diagnosed before 60 years of age.19 Despite this important association. African American and.18.20 Studies have indicated that the highest prevalence of this poor prognosis subgroup is in premenopausal women of African American descent who are 2 to 3 times as likely to have a triplenegative tumor as white women. 3 .

23 Several of the reproductive risk factors Clinically applied risk imply that a DNA damage repair defect may be a funassessment models may damental precursor to triple-negative or basal-like require modification to breast cancers due to their association with increased identify women at high risk proliferation of breast epithelial cells. The primary anthropometric risk factor for triple-negative breast cancer is excess body weight.22 For example. and most BRCA1-related breast cancers show a basal-like phenotype.14 An analysis of data from the North Carolina Central Cancer Registry (NCCCR). Triple-negative breast cancer occurs more often in overweight women. 39% of premenopausal African American women compared with 14% of postmenopausal African American women and 16% of non–African American women.21.10 Heredity Familial and hereditary associations with triple-negative breast cancer suggest that genetics influence the etiology of these tumors. for the development of triple-negative breast cancer. Biologic. a higher prevalence of triplenegative breast cancer appears to exist among patients with the BRCA1 mutation. it may relate to insulin resistance and increased mitotic activity in breast epithelial tissue.10 Differences in risk factors between African American and white women were particularly strong when the women were 4 . and 1564 control cases enrolled during the years 1993 through 2001. 80% were identified as having triple-negative breast tumors.10.24 for triple-negative breast Premenopausal status is another known risk factor cancer.18 Triple-negative breast cancer was found in 24% of premenopausal women compared with 15% of postmenopausal women.Triple-Negative Breast Cancer Understanding the Molecular. shorter duration of breastfeeding.10. as defined by a high waist-to-hip ratio or abdominal adiposity.21 The mechanism underlying the impact of obesity on triple-negative breast cancer risk is unclear.25 A recent analysis of the 482 breast cancer patients with marker data available found that among those with the BRCA1 mutation. a greater percentage of patients with triple-negative breast cancer had strong family histories of breast cancer and were more likely to be of African American descent than those who had other breast cancer subtypes. which included 1803 breast cancer cases. The Carolina Breast Cancer Study (CBCS) found this breast cancer subtype to be more prevalent among premenopausal women in general and premenopausal African American women in particular. and Clinical Characteristics multiple births. lower incidence of breastfeeding. and greater use of lactation suppressants.14 In addition.22 The association between the risk of triplenegative breast cancer and having had several children or giving birth at a young age is in contrast to the greater risk of breast cancer in general in women who never had children or had their first full-term pregnancy at age 30 or older. found that some risk factors for triple-negative breast cancer may be associated with racial background.

0003 7% P = .31 P <.04 9% 37% 14% P <.subdivided into 2 age groups (Table 1). Recent analysis indicates that encouraging those at higher risk to increase breastfeeding. Justification also exists for reducing the risks of triple-negative breast cancer. lose weight.0001 5 . and increase physical activity Table 1.0001 42% P = .0001 55% P = . had breastfed fewer children.0001 26% P <. Distribution of Selected Triple-Negative Breast Cancer Risk Factors by Race and Age10 Risk Factor African American Aged <40 yr 24% White Aged <40 yr 13% African White American Aged 40-49 yr Aged 40-49 yr 41% 19% Parity ≥3 Never breastfed Parity ≥3 and never breastfed Lactation suppressants.0001 61% P = .10 Influencing Risk Clinically applied risk assessment models may require modification to identify women at high risk for triple-negative breast cancer. had children before age 24.0001 9% 39% 10% P <.0003 61% P = .0001 61% 46% 80% P <.06 78% 59% 86% P = .0001 27% P <.77 P = . ever use Parous women: age at first-term pregnancy <26 years Parous women ≥2 children breastfed ≥4 months breastfeeding per child Waist-to-hip ratio ≥.01 18% 5% 30% 61% 75% P = .002 34% 19% 61% P <. The CBCS found that triple-negative breast cancer was significantly more common among women of African American descent who had given birth to 3 or more children. and had breastfed fewer months overall.45 82% P = .

5 6 .Triple-Negative Breast Cancer Understanding the Molecular.10 For example.24 Breast Cancer Phenotypes Recently. achieved using DNA microarray analysis." triple-negative breast cancer and basal-like breast cancer refer to 2 different entities.26 In practice. In the NCCCR analysis. breast cancers have been robustly categorized and divided into distinct subtypes based on gene expression.5. while basal-like breast to 2 different entities. PR.27 The term "basal-like interchangeably with the breast cancer" describes a rigorously defined subtype term “basal-like breast with specific gene expression. These groups overlap significantly and share important similarities.” triple-negative breast cancer and basal-like negative breast cancer is determined using clinical breast cancer actually refer assays for ER. public health interventions targeted towards reducing obesity in high-risk populations may help reduce the risk of triple-negative breast cancer in selected populations. if the 2 most easily modified risk factors (breastfeeding and elevated waist-to-hip ratio) were eliminated. PR-. are certainly worthwhile and are being pursued. Biologic. or immunohistochemistry (IHC). the terms are not Although often used necessarily interchangeable. or HER2 receptors. luminal C. however.24 Although often used interchangeably with the term "basallike breast cancer. triplecancer. PR.4. The tumor is said to be ER-. though difficult to achieve. approximately 53% of the cancers with this high-risk disease might have been avoided in the overall population. and HER2. and HER2-negative based on easily available immune assays. a characteristic making these tumors more similar to the basal-like and ERBB2+ subtypes and slightly less similar to the luminal A and luminal B subtypes.7 Based on gene expression patterns. Molecular Features Defining Triple-Negative Breast Cancer Triple-negative breast cancer is defined as the absence of ER.26. and Clinical Characteristics may be beneficial. is sometimes distinguished from luminal A and luminal B tumors by an elevated expression of a unique set of genes of unknown function. an immediate need exists for research targeted at improving survival through a better understanding of the molecular features and basic science of triple-negative breast cancer. cancer describes a phenotype determined using genetic characterization or more comprehensive profiling.10 While efforts to influence population behaviors. breast cancers have been divided into 5 distinct groups: I Luminal A I Luminal B I HER2+/ERI Basal-like I Normal breast-like (Figure 2)5 A sixth subtype. or molecular phenotypes.

Logically. Proc Natl Acad Sci U S A. Perou CM.S. Expression levels of these genes further correlate with the mitotic index observed in a tumor.13. and most are classified as triple-negative breast cancers.4 For example. known as the "proliferation cluster.29 Although this indicates that most triple-negative tumors are basal-like.28. there is a 10% to 30% inconsistency between the groups. Clinically. 2001.A. Sorlie T. and the therapeutic targets they express. and cellular composition are aligned with expression of specific gene subsets.28 Of particular relevance to therapeutic decisions.5. a large distinct set of genes.98:10869-10874. Tibshirani R.>8 >6 >4 >2 1:1 >2 >4 >6 >8 Figure 2. activity along a specific signaling pathway.5 DNA microarray analysis allows separation of breast cancers into 5 or 6 distinct subtypes based on gene expression. these different subtypes vary significantly in terms of prognosis. et al." is a group of genes that correlates with cellular proliferation rates.5 Basal-like Breast Cancer The poor prognosis basal-like phenotype accounts for approximately 15% of breast cancers. and conversely most basal-like tumors have been found to exhibit triple-negative profiles.5 An analysis of 88 evaluable triple-negative tumors revealed that 91% also were classified as basal-like tumors using microarray analysis. Basal-like breast tumors specifically NEW YORK 3 STANFORD 48 NORWAY 21-BE NORWAY 37-AF NORWAY 41-BE STANFORD 14 STANFORD 46-LN STANFORD 23 NEW YORK 2 NORWAY 81-AF NORWAY H5 NORWAY 63-BE NORWAY 109-BE NORWAY 80-BE NORWAY 14-BE NORWAY 65-2ndT STANFORD 2 NORWAY 53-BE NORWAY 101-BE NORWAY 57-BE NORWAY 47-BE NORWAY H6 STANFORD 16 STANFORD 45 STANFORD 44 NORWAY 55-BE Benign STF 37 NORWAY 112-BE NORWAY 65-BE NORWAY 61-BE NorwNormBrst1 NormBrst3 NormBrst2 NormBrst1 Benign STF 20 Benign STF 11 NORWAY H2 NORWAY 104-BE NORWAY 48-BE NORWAY 102-BE NORWAY 26-BE NORWAY 11-BE NORWAY 19-BE NORWAY 15-BE NORWAY 95-BE NORWAY 22-BE NORWAY 7-BE NORWAY 51-BE NORWAY 10-BE NORWAY 39-BE NORWAY 17-BE NORWAY 100-BE NORWAY 12-BE NORWAY 83-BE NORWAY 96-AF NORWAY 90-BE NORWAY 85-BE NORWAY H4-T1 NORWAY 43-AF NORWAY 32-BE NORWAY 4-BE NORWAY 111-BE NORWAY 27-BE NORWAY 18-BE STANFORD 24 NORWAY 74-BE NORWAY 16-BE NORWAY 56-BE NORWAY 64-BE NORWAY 8-BE NORWAY 6-BE NORWAY 98-BE NORWAY 24-BE NORWAY H3 STANFORD A NEW YORK 1 STANFORD 6 STANFORD 40 STANFORD 18 STANFORD 4-LN STANFORD 35 STANFORD 38 STANFORD 31 STANFORD 17 NORWAY 29-BE Basal-like ERBB2+ Normal Breast-like Luminal Luminal Subtype C Subtype B Luminal Subtype A 7 . U. impacts on growth rate. Copyright 2001 National Academy of Sciences. these tumors typically have low expression of ER and HER2. Gene expression patterns depicting the phenotypic breast cancer subtypes.29 Other aspects of the basal-like breast cancer phenotype are noteworthy and the observed genetic characteristics of basal-like tumors may hold biologic implications. the basal-like phenotype stands out as the genetic profile with the shortest survival times and worst prognosis. outcomes.

expressed a p53 mutation compared with only 13% in tumors of the luminal A phenotype. Potential therapeutic targets for this disease include EGFR or c-KIT. as cells with an already impaired DNA repair function may have an innate sensitivity to certain systemic agents. including cytokeratins 5.5 In addition to p53 mutations. 88% were identified as basallike breast cancers (OR = 9.4 Basal-like cancers express HER1/EGFR more often than other subtypes.30 HER1 is relevant not only as a potential molecular target.28 In addition to HER1/EGFR and c-KIT.002).25.6. It has been hypothesized that this instability contributes to the predisposition for malignancy in patients with mutations that remove BRCA1 function. with this marker present in as many as 60% of basal-like breast cancers. Not only is BRCA1 mutation one of the most important forms of hereditary breast cancer.Triple-Negative Breast Cancer Understanding the Molecular. and 17.31 molecular characteristics of these tumors are One study found that 82% of basal-like tumors potentially targetable.9-43. 31% of basal-like tumors stained positive for c-KIT.001). several molecular characteristics of these tumors are potentially targetable.32.13.28 In an analysis comparing basal-like tumors to other breast cancer subtypes. protein kinase components of the mitogen 8 . but is also applicable in identifying basal-like breast cancers.33 A potential therapeutic opportunity may exist for such tumors. The relationship between c-KIT and basal-like breast cancer is also notable.25 Another evaluation of tumors in 18 BRCA1 mutation carriers revealed that 100% of these were basallike breast cancers. another molecule involved in DNA repair. basal-like breast cancer is associated with several other indicaAlthough the full biology of tors of more aggressive tumor behavior such as the triple-negative breast cancer presence of TP53 (p53) mutations. and Clinical Characteristics exhibit a high expression of genes characteristic of the basal epithelial cell layer. several has been linked to the BRCA1 pathway. and the majority of c-KIT-positive breast tumors belong to the basal-like subtype. 1. P = .5.32 BRCA1 is involved in a number of cellular processes. one of which is as part of the DNA damage response.32 In an analysis of 17 specimens from women with BRCA1 mutations. Biologic. tumors in most BRCA1 mutation carriers are classified as a basal-like subtype. and this phenotype remains to be defined.31 This association implies that breast cancers arising in women carrying the BRCA1 mutation may have a similar etiology to basal-like breast cancer.34 Potential Molecular Targets Although the full biology of triple-negative breast cancer remains to be defined. Repair of these lesions must take place using other potentially mutagenic mechanisms that lead to genetic instability.33 Cells that lack BRCA1 or have dysfunctions in this gene are unable to repair DNA double-strand breaks by the normal mechanism of homologous recombination. 95% confidence interval [CI]. is associated with basal-like breast cancers.25.9.31. while this marker was present in only 11% of tumors with other phenotypes (P <. the BRCA1 gene.28. as well as epidermal growth factor receptor (EGFR).30. and c-KIT.28.

PR. ”triple-negative” is sometimes used as a proxy for “basallike” breast cancer in patient care decisions. PR. Because it is easily accessible to clinicians. Heller W.18 ER PR HER2 Negative Positive Positive Negative Luminal A Luminal B HER2+/ERBasal-like ER and/or PR positive ER and/or PR positive Negative Negative Negative Negative ER = estrogen receptor. However. investigators have sought a widely accessible and clinically applicable assay predictive of poor outcome MAP kinase pathway Transcriptional control Akt pathway DNA repair DNA damage Cell cycle Cell death Figure 3. Triple-negative breast cancer: potential therapeutic targets. this technology is not widely available to most clinicians.6.activated protein (MAP)-kinase pathway. and HER2 status (Table 2). a basal-like breast cancer profile can be suggested using other methods for clinical practice. In the absence of full genetic profiling.28 Therefore. PR = progesterone receptor. clinicians can gain an indication of the likely tumor subtype based on the ER. 2007. Genetic Subtype Simplified Receptor Characteristics of Breast Cancer Genetic Subtypes5. and proteins involved in DNA repair such as poly (ADP-ribose) polymerase-1(PARP-1) (Figure 3).13 EGFR tyrosine kinase c-KIT tyrosine kinase Identifying Patients Although gene expression profiling using DNA microarrays is the most reproducible method of identifying the prognostic breast cancer genetic subtypes.8:235-244. 9 . and HER2 staining alone may not identify all basal-like breast cancers due to technical failures during the immunohistochemistry process or because of biologic heterogeneity. identifying basal-like breast cancer based on the absence of ER. Table 2. Lancet Oncol. HER2 = human epidermal growth factor receptor 2. Adapted from Cleator S. protein kinase components of the protein kinase B (Akt) pathway.13 Molecular features of triple-negative breast cancer pose potential therapeutic targets for new therapies. In the absence of DNA microassay or additional basal markers.

24 Expression of selected immunohistochemical markers can be combined A >8 >6 >4 >2 1:1 >2 >4 >6 >8 Figure 4.A. 2001. (B) Microarray results for tissue samples from specimens with selected immunohistochemical profiles. PR. et al. Tibshirani R. Breast cancer subtypes defined by genetic expression and immunohistochemistry. CK14.S. (A) Subtypes based on gene expression.28 These efforts focused on validating that basal-like breast cancer can be identified by a more robust immunohistochemical profile that includes not only ER. and HER2 but also assesses for additional basal markers such as CK5/6. U. and Clinical Characteristics basal-like breast cancers. or EGFR. Perou CM. Biologic.98:10869-10874. Foulkes WD. Winer EP.14:8010-8018. CK17. et al.Triple-Negative Breast Cancer Understanding the Molecular. 2008.28 Adapted and reprinted by permission from the American Association for Cancer Research: Schneider BR. Clin Cancer Res.5 Sorlie T. Copyright 2001 National Academy of Sciences. Proc Natl Acad Sci U S A.7. 10 NEW YORK 3 STANFORD 48 NORWAY 21-BE NORWAY 37-AF NORWAY 41-BE STANFORD 14 STANFORD 46-LN STANFORD 23 NEW YORK 2 NORWAY 81-AF NORWAY H5 NORWAY 63-BE NORWAY 109-BE NORWAY 80-BE NORWAY 14-BE NORWAY 65-2ndT STANFORD 2 NORWAY 53-BE NORWAY 101-BE NORWAY 57-BE NORWAY 47-BE NORWAY H6 STANFORD 16 STANFORD 45 STANFORD 44 NORWAY 55-BE Benign STF 37 NORWAY 112-BE NORWAY 65-BE NORWAY 61-BE NorwNormBrst1 NormBrst3 NormBrst2 NormBrst1 Benign STF 20 Benign STF 11 NORWAY H2 NORWAY 104-BE NORWAY 48-BE NORWAY 102-BE NORWAY 26-BE NORWAY 11-BE NORWAY 19-BE NORWAY 15-BE NORWAY 95-BE NORWAY 22-BE NORWAY 7-BE NORWAY 51-BE NORWAY 10-BE NORWAY 39-BE NORWAY 17-BE NORWAY 100-BE NORWAY 12-BE NORWAY 83-BE NORWAY 96-AF NORWAY 90-BE NORWAY 85-BE NORWAY H4-T1 NORWAY 43-AF NORWAY 32-BE NORWAY 4-BE NORWAY 111-BE NORWAY 27-BE NORWAY 18-BE STANFORD 24 NORWAY 74-BE NORWAY 16-BE NORWAY 56-BE NORWAY 64-BE NORWAY 8-BE NORWAY 6-BE NORWAY 98-BE NORWAY 24-BE NORWAY H3 STANFORD A NEW YORK 1 STANFORD 6 STANFORD 40 STANFORD 18 STANFORD 4-LN STANFORD 35 STANFORD 38 STANFORD 31 STANFORD 17 NORWAY 29-BE Basal-like ERBB2+ Normal Breast-like Luminal Luminal Subtype C Subtype B Luminal Subtype A .

– More likely to be diagnosed as interval cancer • More likely to be found at a later stage of Clinical and Biologic disease Characteristics • Weak association between tumor size and Triple-negative breast cancers have axillary lymph node involvement been characterized by several aggres• Rapid recurrence following diagnosis sive clinicopathologic features. to estimate the different breast cancer phenotypes (Figure 4).18 In addition to 11 . PR. includ– Peak recurrence 1 to 3 years after diagnosis ing later stage at diagnosis. higher • Local recurrence rarely precedes distant average tumor size.17. luminal B.Table 3. Specifically. in this system. and a high • Majority of deaths occur within 5 years prevalence of tumors with unfavorable of diagnosis histology (Table 4).9. PR = progesterone receptor. basal-like breast cancer phenotype. Validated Refined IHC Profile for Breast Cancer Subtypes18 Genetic Cytokeratin ER PR HER2 HER1 5/6 Subtype Luminal A Luminal Ba HER2+/ERBasal-like ER and/or PR positive ER and/or PR positive Negative Negative Negative Negative Negative Positive Positive Negative Positive for either or both ER = estrogen receptor. high mitotic index. as only 30% to 50% are HER2+. HER2-. HER1 = human epidermal growth factor receptor 1. and basal-like breast examination or clinical examination cancer phenotypes. this system combines ER. The investigators found that not only did the profile defined by ER-. the survival outcomes of patients with this immunohistochemical profile also correlated with the poorer survival outcomes seen with the Table 4. • More likely to be found by breast selfHER2+/ER-. aThis definition of luminal B does not identify all luminal B tumors.28 Clinicopathologic Features Table 3 summarizes the refined of Triple-Negative Breast Cancer immunohistochemical profiling system that predicts the luminal A. higher-grade recurrence tumors.28 A pivotal validation of this profiling method evaluated a panel of 21 genetically confirmed basal-like tumors. and/or HER1+ consistently correlate with basal-like breast cancer. and HER2 status with the additional basal markers CK5/6 and/or HER1 added to the profile to predict the presence of the basal-like breast cancer phenotype.18. HER2 = human epidermal growth factor receptor 2. cytokeratin 5/6+. those would be classified as luminal A.

and Clinical Characteristics more aggressive features.35 These so-called “interval” tumors present a challenge to early detection and treatment.40 (P = . women with triple-negative disease presented breast cancer have a more with a more advanced stage of disease. patients with triple-negative breast cancer. ated.0408) 0. triple-negative breast cancer is more likely to be detected through clinical examination or patient self-detection than imaging.0001) 10.358 California women diagnosed with breast cancer between 1999 Women with triple-negative and 2003.0450) 1.9 Table 5. >2 vs ≤2 cm Grade.17 (P <.0 1.0004) 0.0001) 1.0 1. 76% of the triple-negative breast pared with women with cancers in this series were classified as poorly differentiother breast cancer subtypes.0001) 1. positive vs negative aIncludes Triple-negative/ Basal-like HER2 Luminal B (Referent) 1.85.0001) compared to luminal A tumors (Table 5). while only 26% of other tumor subtypes were classified as poorly differentiated. had a significantly shorter 3-year disease-free and overall survival.0 1. P <.Triple-Negative Breast Cancer Understanding the Molecular.0001) 0.23 (P <.0008).0001) lobular mixed and pure lobular carcinomas.0001) 9. and the median aggressive clinical course tumor size in this group was significantly larger than in and inferior outcomes comother patients.0% of patients with other breast cancer subtypes (P = .38 (P <.17.0 Luminal A 0. The study found that triple-negative tumors were more likely to exhibit p53 positivity (OR = 4.05 (P <.0001) 0.22 (P = .19. 95% CI. as well as those with HER2-positive tumors.01-5.5436) 14. conducted to compare chemotherapy regimens in patients with node-positive breast cancer.19 (P <.13 (P = . In one large analysis of data from 92. 12 .0001) 4.17 Similar findings were reported in a population-based study.19 (P <. 3.0 1.8 The association between more aggressive features and the triple-negative subtype was also observed in a subset analysis of data on 1350 patients in the Breast Cancer International Research Group (BCIRG) 001 trial.73 (P = .3871) 4. Biologic.0001) 4. In this study.35 In a cohort of 1601 patients diagnosed between 1987 and 1997. Further.50 (P <. 19. ductal vs lobulara Size.61 (P <. Odds Ratio for Tumor Characteristics by Biologic Subtype9 Characteristic Type.46 (P = . positive vs negative P53. 3 vs 1+2 Vascular invasion. possibly due to more rapid growth or differences in the ability to detect these tumors.11 (P = .6% of triple-negative tumors were detected by mammography or ultrasound versus 36.5612) 1.74 (P <.

aggressiveness of triple117 of whom had triple-negative disease (Table 6). patients with triple-negative breast cancer tend to relapse more rapidly.14 Local recurrences were not significantly difafter diagnosis. even when adjusted for stage and race. with a higher percentage of distant metastases and worse disease-free survival than patients with other breast cancer subtypes.16.8.14-16 Survival outcomes reported in triple-negative breast cancer are substantially worse compared with other breast cancer subtypes. usually between the first and third year after diagnosis.17. and declining 13 . Triple-negative (N = 117) 83% 94% 68% 72% Other Subtypes (N = 365) 83% 99% 83% 85% P Value NS . peaking at approximately 3 years.047 Recurrence Women with triple-negative breast cancer have a more aggressive clinical course and inferior outcomes compared with women with other breast cancer subtypes. the risk of triple-negative breast cancer recurrence rose sharply following diagnosis.002 . and disease-free survival between those with triple-negative disease and other the first and third year subtypes.36 A recent study compared outcomes among 1601 patients with breast cancer. while the risk of recurrence for other breast cancers generally is constant over time.Table 6.17 In this series. 5-Year Breast Cancer–Related Outcomes in a Series of 482 Women With Triple-Negative Disease14 Outcome Breast relapse-free rate Nodal relapse-free rate Distant metastasis-free rate Cause-specific survival rate NS = not significant.17 This difference in breast cancer–related outcomes was demonA hallmark of the strated in a series of 482 women with breast cancer. negative breast cancers is that these tumors most often This study confirmed significant differences in nodal recur early. distant metastasis. Clinical studies report consistently shorter disease-free intervals following therapy for women with triplenegative disease than for those with other breast cancer subtypes. ferent between the 2 groups. Recurrence Patterns A hallmark of the aggressiveness of triple-negative breast cancers is that these tumors most often recur early. usually between relapse. 180 of whom had triple-negative disease.14.05 .15 In general.

Biologic. and a set of genes has been identified that provides metastatic cells with advantages in the lung microenvironment.17 The likely location of triple-negative breast cancer metastasis has been linked to biologic features and pathways specific to the basal-like subtype. the triple-negative subset had a significantly increased likelihood of distant recurrence (hazard ratio [HR]. although these patients are less likely to relapse with bone metastases. decreased survival following recurrence is observed regardless of the site of the recurrence.5.0-3. but occurred less than expected in the basal-like phenotype (P = . 2. visceral.9% of patients with triple-negative breast cancers experiencing distant recurrence compared to 20. and central nervous system metastases. including lung. Consistent with the overall higher risk of recurrence in the first years after therapy. women with triple-negative breast cancers have a shorter Women with triple-negative median survival time.37 Bone relapse occurred most often in the luminal A subtype.17 This women with other subtypes. and there was also a strong predilection for brain metastasis in the patients 14 . Women with triple-negative breast cancer also have a higher risk of death earlier after diagnosis than women with other subtypes.37. Conversely. 95% CI.6.40 Genetic assessment of an intrinsic gene list in 344 patients classified with the different breast cancer subtypes revealed site-specific recurrence patterns. while other subtypes continued to accrue deaths up to 18 years after diagnosis.40 In-depth analysis has revealed that gene expression patterns for a particular breast cancer subtype.0001). P <. Patients with this aggressive subtype are more likely to recur with distant metastases.4% in women with other breast cancers. One series documented only breast cancer also have a 9 months postrecurrence survival for women with higher risk of death earlier triple-negative breast cancer compared to 20 months after their diagnosis than for those with other subtypes of breast cancer. and Clinical Characteristics thereafter. lung metastasis occurred more frequently in the basal-like subtype (P = . the mean time to these distant metastases was 2.0001). survival. share biology with the preferred metastatic site for that subtype.37 Specific signaling pathways and chemokines contribute to homing. 2. these areas exert different requirements for circulating cancer cells to establish metastases.Triple-Negative Breast Cancer Understanding the Molecular.01) than in other subtypes. For example.17 By 10 years of follow up. and proliferation of tumor cells in their new site. facilitating metastasis to specific areas.17. One series observed that all triple-negative breast cancer–related deaths occurred within the first 10 years.36 Once a recurrence occurs. with 33. Both 3.and 5-year survival has been reported to be shorter for women with triple-negative breast cancer. such as the basal-like group. the differences in recurrence between triple-negative breast cancer and other subtypes are reduced. while other subtypes experienced distant recurrences at a mean of 5 years (P <.0001).36 The location of recurrence also is markedly different between triple-negative breast cancers and other phenotypes. although bone and lung are common sites of breast cancer metastasis.36-39 In one study.6 years for those with triple-negative breast cancer.

with triple-negative breast cancer (P = .42 Triple-negative breast cancers do not express hormone or HER2 receptors. chemotherapy is the only systemic treatment option available for these women. and extended diagnostics for these distant recurrences might be warranted. A retrospective analysis of data from 3193 breast cancer patients found that women with triple-negative breast cancers had the highest risk of developing cerebral metastasis among all subtypes. the negative prognostic profile correlated to the aggressive disease definition of basal-like breast cancer. a set of classic negative prognostic factors (70-gene both in the adjuvant and profile. recurrence score. Current therapeutic options based on receptor status.0035). c-KIT. chemotherapy remains the only systemic therapy option for these patients in the adjuvant and metastatic settings (Figure 5).38 Prognostic Factors Triple-negative breast cancer is potentially associated At present. the optimal ER/PR Positive HER2 Positive & ER/PR Positive HER2-Targeted Therapy Hormonal Therapy Chemotherapy Chemotherapy Chemotherapy HER2 Positive HER2 Negative & ER/PR Negative Hormonal Therapy HER2-Targeted Therapy Chemotherapy Figure 5. and p53. 15 .13 Thus.28. rendering current hormonal and HER2-targeted therapies ineffective. 41 Clinical Management Current Clinical Practices Based on the absence of hormonal receptors and the HER2 receptor.30 When option for these patients. Thus. signature) were applied to a series of genetically determined basal-like breast cancers. chemotherapy is with several markers of more aggressive tumors the only systemic therapy including HER1 (EGFR). activated wound response metastatic settings.41 The authors concluded that these classic prognostic parameters likely identified a set of biologic properties common in basal-like breast cancer as well.42 However. suggesting that this adds a generally even poorer prognosis for these patients. triple-negative breast cancer is by definition minimally responsive to treatments targeting these receptors.

5 cm to ≤1 cm). despite a lack of definitive evidence.13.44 One registry study indicated than even in breast cancer patients with small tumors (>0.34). those with triple-negative disease were more likely to receive aggressive adjuvant chemotherapy. 16 . combination and sequential chemotherapeutic regimens are hypothesized to be logical strategies for triple-negative breast cancer. 95% CI = 2. In clinical practice. Although the full emphasize the necessity for pathways driving proliferation of triple-negative breast new treatment modalities cancers remain to be identified.44 outcomes in women with Overall. lung. patients with triple-negative breast cancer pose significant clinical management challenges.13 Despite this. Conclusion Triple-negative breast cancer is clinically relevant as a discrete breast cancer subtype based on its unique profile in terms of poor prognosis and aggressive metastatic behavior. and Clinical Characteristics regimen for these women is not known and no established guidelines for the selection of specific agents are available. patients with triple-negative disease tend to be treated more aggressively than patients with other breast cancer subtypes. clinicians must remain vigilant for this aggressive breast cancer subtype with its potential for earlier recurrence patterns and propensity for distant metastasis to the brain.14-17 In the adjuvant setting.42.44 Despite this more aggressive treatment. Biologic. for this disease. triple-negative patients have a significantly greater The established poor risk of recurrence (HR. women with triple-negative breast cancer generally experience systemic recurrences earlier and have poorer survival than women in other breast cancer subgroups. 6.43 Treatment decisions for women with triple-negative breast cancer rely on a clinical judgment and individual patient considerations. Although representing only 10% to 15% of all breast cancers.Triple-Negative Breast Cancer Understanding the Molecular. as well as its unique molecular and genetic features. as no targeted therapy for them is available. Ongoing progress in understanding the molecular science behind triple-negative breast cancer is potentially a route to optimizing outcomes for women with this breast cancer subtype. and other visceral sites. the established poor outcomes in women triple-negative breast cancer with triple-negative breast cancer emphasize the treated with today's necessity for new treatment modalities targeting the conventional chemotherapies specific biology of this phenotype. including PARP-1 are being investigated of this phenotype. Currently.57. several potential thertargeting the specific biology apeutic targets.

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